Abstract

Background

Although it has long been proposed that genetic factors contribute to adaptation to
high altitude, such factors remain largely unverified. Recent advances in high-throughput
sequencing have made it feasible to analyze genome-wide patterns of genetic variation
in human populations. Since traditionally such studies surveyed only a small fraction
of the genome, interpretation of the results was limited.

Results

We report here the results of the first whole genome resequencing-based analysis identifying
genes that likely modulate high altitude adaptation in native Ethiopians residing
at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population
tests of selection, we identify regions with a significant loss of diversity, indicative
of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which
is significant in both of the Ethiopian subpopulations sampled. This region contains
eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in
hypoxia tolerance, we experimentally tested whether individual genes from the region
affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3.

Conclusions

Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance.
In addition, we show that many of our results would likely be unattainable using data
from exome sequencing or microarray studies. This highlights the importance of whole
genome sequencing for investigating adaptation by natural selection.